Mitotic signaling by β‐amyloid causes neuronal death

Abstract

Aggregates of beta-amyloid peptide (betaAP), the main constituent of amyloid plaques in Alzheimer's brain, kill neurons by a not yet defined mechanism, leading to apoptotic death. Here, we report that both full-length betaAP((1-40)) or ((1-42)) and its active fragment betaAP((25-35)) act as proliferative signals for differentiated cortical neurons, driving them into the cell cycle. The cycle followed some of the steps observed in proliferating cells, including induction of cyclin D1, phosphorylation of retinoblastoma, and induction of cyclin E and A, but did not progress beyond S phase. Inactivation of cyclin-dependent protein kinase-4 or -2 prevented both the entry into S phase and the development of apoptosis in betaAP((25-35))-treated neurons. We conclude that neurons must cross the G1/S transition before succumbing to betaAP signaling, and therefore multiple steps within this pathway may be targets for neuroprotective agents.-Copani, A., Condorelli, F., Caruso, A., Vancheri, C., Sala, A., Giuffrida Stella, A. M., Canonico, P. L., Nicoletti, F., Sortino, M. A. Mitotic signaling by beta-amyloid causes neuronal death.

DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease

“…The source of the signal that drives the neurons in Alzheimer's disease to begin the process thus becomes a question of utmost importance. The ␤-amyloid peptide itself has been shown to be capable of driving cell division and cell death in cultured neurons (Copani et al, 1999); in a similar assay, conditioned medium from ␤-amyloidstimulated microglial cells can also trigger neuronal cell division leading to cell death (Giovanni et al, 1999;Wu et al, 2000). These latter data are particularly intriguing given the epidemiological findings of a protective effect of high doses of nonsteroidal anti-inflammatory drugs (P. McGeer and McGeer, 1995;E.…”

“…During this same developmental period, if cell cycle reentrance is forced by ectopically driving an oncogene with a neuronal-specific promotor, the targeted neurons will die rather than divide (al-Ubaidi et al, 1992;Feddersen et al, 1992). Several in vitro cell death models have illustrated the same correlation (Park et al, 1997Copani et al, 1999;Giovanni et al, 1999Giovanni et al, , 2000Wu et al, 2000).…”

Src kinase inhibition decreases thrombin-induced injury and cell cycle re-entry in striatal neurons

“…Although it appears that they face continuing stress to re-enter the cell cycle, a series of anti-growth factors prevent them from normally doing so (Copani and Nicoletti, 2005). A growing number of in vivo and in vitro studies, however, show that post-mitotic neurons can re-enter the cell cycle after brain injury in rat and humans (Hayashi et al, 2000, Copani et al, 2001, Love, 2003, Becker and Bonni, 2004, Greene et al, 2004, Herrup et al, 2004, Kuan et al, 2004, Di Giovanni et al, 2005, Copani et al, 1999, Liu and Greene, 2001, Rao et al, 2007. This cell cycle re-entry is a critical element of the DNA damage response of post mitotic neurons leading to apoptosis (Kruman et al, 2004).…”

Alzheimer disease and neuroplasticity: New approaches and new targets in pharmacotherapy

“…Aβ appears to drive this abnormal and ultimately fatal cell cycle entry. In primary neuronal culture, neurons treated with Aβ have increases in expression of cyclins, begin DNA replication, then undergo apoptosis in a cyclin-dependent manner (79,88).…”

“…In early AD, several growth-related proteins are upregulated, which may reflect attempts to stimulate plasticity, including growth-associated protein 43 (GAP-43), myristoylated alaninerich C kinase substrate (MARCKS), spectrin, heparansulfate, laminin, neural cell adhesion molecule (NCAM), various cytokines and neurotrophic factors including nerve growth factor (NGF), fibroblast growth factor (bFGF), epidermal growth factor (EGF), interleukin (IL) 1, 2 and 6, insulin-like growth factor 1 (IGF-1), IGF-2, platelet-derived growth factor (PDGF), Hepatocyte growth factor (HGF), and several growth factor receptors (88). Deregulations of proteins involved in structural plasticity of axons and dendrites indicate a failure of plasticity mechanisms, and support a disruption of synapse turnover as a primary mechanism in AD (15,89).…”